EP0976700B1 - Procede d'halogenation de groupe hydroxyle - Google Patents

Procede d'halogenation de groupe hydroxyle Download PDF

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Publication number
EP0976700B1
EP0976700B1 EP98959149A EP98959149A EP0976700B1 EP 0976700 B1 EP0976700 B1 EP 0976700B1 EP 98959149 A EP98959149 A EP 98959149A EP 98959149 A EP98959149 A EP 98959149A EP 0976700 B1 EP0976700 B1 EP 0976700B1
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group
compound
ion
chain
formula
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EP0976700A4 (fr
EP0976700A1 (fr
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Daisuke Otsuka Kagaku Kabushiki Kaisha Suzuki
Ryo Otsuka Kagaku Kabushiki Kaisha KIKUCHI
Masaru Otsuka Kagaku Kabushiki Kaisha Yasui
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Otsuka Chemical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C257/00—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines
    • C07C257/02—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by halogen atoms, e.g. imino-halides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B39/00—Halogenation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C17/00—Preparation of halogenated hydrocarbons
    • C07C17/093—Preparation of halogenated hydrocarbons by replacement by halogens
    • C07C17/16—Preparation of halogenated hydrocarbons by replacement by halogens of hydroxyl groups

Definitions

  • the invention relates to a method of preparing a halogenated compound using a halogenating agent.
  • the halogenating method of the invention enable high purity and high yield production of halogenated aromatic compounds, halogenated heterocyclic compounds and halogenated cholesterol derivatives, each being useful for an intermediate for medicine and agricultural chemical, and also 7-acylamide-3-halocephem derivative useful for general cephem antibiotics used by oral administration.
  • Journal of Synthetic Organic Chemistry, 1980, 746 discloses a method in which dimethylformamide is reacted with oxalyl dichloride to obtain dimethyl chloroiminium compound, and hydroxyl group bonded to a straight-chain alkyl group is chlorinated by using the above chloroiminium compound.
  • this method a 90 % yield is achieved, however, such a high yield is not always obtained.
  • the purity of the resulting halogenide is about 80 % at the most, and the reaction time is extremely long, namely, 24 hours.
  • a dimethyl haloiminium compound is also used in preparing N-acyl-4-chloro-1,2-dihydropyridine which is an intermediate for alkaloid [J. Org. Chem. (1993) 58, 7732-7739]. This method is, however, impractical because the reaction time is markedly long, namely, three days.
  • An object of the invention is to overcome the drawbacks of long reaction time, unstable yield, low purity, and the formation of by-product obtained by halogenation of other than the desired hydroxyl group, which drawbacks are common to the methods of halogenating a hydroxyl group by using a dimethyl haloiminium compound or diphenyl haloiminium compound.
  • the invention relates to a method of preparing a halogenated compound of formula (3) A-X wherein A is a straight-chain or branched-chain alkyl group which may be substituted, a straight-chain or branched-chain alkenyl group which may be substituted, a monocyclic or polycyclic aromatic residue which may be substituted, a steroid residue, or a monocyclic or polycyclic heterocyclic residue which may be substituted, and X is a chlorine atom or a bromine atom, which comprises reacting in an organic solvent at least one halogenating agent of formula (1) wherein X is as defined above and Y is a chlorine ion, bromine ion, dichlorophosphate ion, dibromophosphate ion, chlorosulfonate ion, bromosulfonate ion, chlorooxalate ion or bromooxalate ion, with a hydroxyl group containing compound of formula (2) A -
  • compounds obtained by halogenation of a hydroxyl group can be produced at high yield and high purity in a short period of time.
  • the halogenating agent of the invention when used, only the hydroxyl group is selectively halogenated, irrespective of the structure of the hydroxyl group containing compound and the kind of substituent other than hydroxyl group.
  • the acyl group at the 7-position and lactam part are not halogenated, and only the hydroxyl group at the 3-position is selectively halogenated. Therefore, the desired halogenide can be produced at high yield and high purity, and the reaction time is short.
  • halogen atom examples include chlorine atom and bromine atom.
  • C 1 -C 4 alkyl group are straight-chain or branched-chain alkyl groups, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl.
  • C 2 -C 8 alkenyl group are straight-chain or branched-chain alkenyl groups, such as vinyl, propenyl, butenyl, pentenyl, hexenyl, isopropenyl, isobutenyl, isopentenyl, octenyl and isoprenyl.
  • Examples of monocyclic or polycyclic aromatic hydrocarbon group are phenyl group, naphthalene group and anthracene group.
  • Examples of monocyclic or polycyclic heterocyclic hydrocarbon group are furyl group, pyrrolyl group, thienyl group, oxazolyl group, imidazolyl group, thiazolyl group, pyridyl group, pyrazyl group, pyridazyl group, morpholinyl group, quinolyl group, isoquinolyl group, indole group, indolizyl group, penicillin residue and cephalosporin residue.
  • Examples of steroid residue are androsterone residue, testosterone residue and cholesterol residue.
  • C 1 -C 15 alkyl group are straight-chain, branched-chain or cyclic alkyl groups, such as methyl, ethyl, propyl, butyl, isopropyl, isobutyl, tert-butyl, hexyl, cyclohexyl and pentadecanyl.
  • substituted oxycarbonyl group examples include bromobutoxycarbonyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, benzyloxycarbonyl and allyloxycarbonyl.
  • acyl group examples are formyl, acetyl, propionyl, butyryl, valeryl, benzoyl, toluoyl and naphthoyl.
  • amido groups such as phenoxyacetamido, p-methylphenoxyacetamido, p-methoxyphenoxyacetamido, p-chlorophenoxyacetamido, p-bromophenoxyacetamido, phenylacetamido, p-methylphenylacetamido, p-methoxyphenylacetamido, p-chlorophenylacetamido, p-bromophenylacetamido, phenylmonochloroacetamido, phenyldichloroacetamido, phenylhydroxyacetamido, thienylacetamido, phenylacetoxyacetamido, ⁇ -oxophenylacetamido, benzamido, p-methylbenzamido, p-methoxybenzamido, p-chlorobenzamido, p-bromophenoxyaceta
  • Ri and Rj are same or different and each a hydrogen atom, C 1 -C 15 alkyl group, aromatic hydrocarbon group or heterocyclic hydrocarbon group, or may bond together to form a cyclic group.
  • C 1 -C 15 alkyl group, aromatic hydrocarbon group and heterocyclic hydrocarbon group are the same as given above.
  • examples of the aforesaid cyclic group are C 4 -C 8 cycloalkyl group (e.g., cyclobutyl, cyclohexyl, cyclooctyl, etc), including carbon bonded to N, and aromatic groups (e.g., phenyl, tolyl, naphthyl, etc.)
  • lower alkoxy group are straight-chain or branched-chain C 1 -C 4 alkoxy group, such as methoxy, ethoxy, n-propoxy, isopropoxy, sec-butoxy and tert-butoxy.
  • cyclic amino protecting group are phthaloyl group and nitrophthaloyl group.
  • Examples of the protective group for carboxylic acid are allyl group, benzyl group, p-methoxybenzyl group, p-nitrobenzyl group, diphenylmethyl group, trichloromethyl group, trichloroethyl group and tert-butyl group, in addition to a variety of groups as described in the fifth chapter of the aforesaid literature (pages 152-192).
  • the diethyl haloiminium compound of the formula (1) can be produced, for example, by allowing diethylformamide to react with a halogenating agent in an organic solvent.
  • the organic solvent used herein is not limited specifically insofar as it does not cause adverse effect on the reaction between the diethylformamide and the halogenating agent.
  • lower alkyl esters of lower carboxylic acid such as methyl formate, ethyl formate, propyl formate, butyl formate, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, methyl propionate and ethyl propionate
  • ketones such as acetone, methyl ethyl ketone, methyl propyl ketone, methyl butyl ketone, methyl isobutyl ketone and diethyl ketone
  • ethers such as diethyl ether, ethyl propyl ether, ethyl butyl ether, dipropyl ether, diisopropyl ether, dibutyl ether, methyl cellosolve and dimethoxye
  • organic solvents may be used singly or in a combination of at least two of them. If desired, these organic solvents may be previously dehydrated prior to use by molecular sieves, for example. Although the amount of organic solvent is not limited specifically, it is usually about 1 to 100 liters, preferably about 5 to 50 liters, per 1 kg of diethylformamide.
  • halogenating agent any one known in the art can be used. There are, for example, phosgene, oxalyl dichloride, thionyl chloride, phosphorus pentachloride, phosphorous trichloride, phosphorus oxychloride, carbonyl dibromide, oxalyl bromide, thionyl bromide, phosphorous bromide and phosphorus oxybromide.
  • the halogenating agents can be used singly or in a combination of at least two of them. Although the amount of halogenating agent is not specifically limited, it is usually 0.5 to 10 equivalents to dialkyl formamide or diallyl formamide. If necessary, the halogenating agent may be further added until the diethyl formamide is exhausted.
  • the above reaction is usually conducted at temperatures of about -78 to 60 °C, preferably about 0 to 30 °C, and the reaction is usually completed in about 0.5 to 20 hours, preferably about 0.5 to 8 hours.
  • the reaction mixture is purified by the usual means such as concentration, thereby isolating the halogenating agent of the invention (diethyl haloiminium compound).
  • the reaction mixture containing the halogenating agent of the invention can be directly used, without purification, for the halogenating reaction of hydroxyl group.
  • halogenide (3) halogenides of the following formula (3) (hereinafter referred to as "halogenide (3)") are produced by reacting at least one of the halogenating agents of the formula (1) (hereinafter referred to as “halogenating agent (1)”) with a hydroxyl group containing compound of the following formula (2) (hereinafter referred to as "hydroxyl containing compound (2)”) in an organic solvent A-OH wherein A is a straight-chain or branched-chain alkyl group which may be substituted, a straight-chain or branched-chain alkenyl group which may be substituted, a monocyclic or polycyclic aromatic residue which may be substituted, a steroid residue, or a monocyclic or polycyclic heterocyclic residue which may be substituted A-X wherein A and X are the same as above.
  • the hydroxyl group containing compound is not specifically limited, and any organic compounds which has a hydroxyl group in the molecule can be used. There are, for example, the following compounds (5) through (11). Examples of substituent are aryl group and lower alkoxycarbonyl group. Examples of the lower alkoxy group of the lower alkoxycarbonyl group are alkoxy group having 1 to 4 carbon atoms.
  • Compounds (5) to (10) are preferred, Compounds (7) to (10) are more preferred, Compounds (9) and (10) are most preferred, and Compound (10) is the best.
  • organic solvent those which are used in producing the halogenating agent (1) of the invention (the above-mentioned ones) can be used. It is also possible to use amides containing dimethylacetoamide, dimethylimidazolidinone and a cyclic amide such as N-methyl-2-pyrrolidone. They can be used solely or in a combination of at least two of them.
  • the amount of organic solvent is not specifically limited and can be selected appropriately from a wide range. It is, however, usually about 1 to 200 liters, preferably about 5 to 20 liters, per 1 kg of the hydroxyl group containing compound (2).
  • the amount of the halogenating agent (1) is not specifically limited and can be selected suitably from a wide range. It is, however, usually 0.1 to 10 equivalents, preferably 0.5 to 2.0 equivalents, to the hydroxyl group containing compound (2).
  • the halogenating compound (1) may be added, as required, until the hydroxyl group containing compound (2) in the reaction system is exhausted.
  • the above reaction is conducted with or without stirring, usually at temperatures of about -78 to 60 °C, preferably about 0 to 30 °C, and the reaction is usually terminated in about 0.5 to 20 hours, preferably about 0.5 to 8 hours. If necessary, the reaction can also be conducted in a sealed container or in the presence of an inert gas, e.g., nitrogen gas.
  • the resulting halogenide (3) is easily isolated by the usual purification operation, such as concentration, distillation, chromatography and crystallization.
  • reaction mixture was further stirred at room temperature for 6 hours, and this was poured into 1 liter of ice water and then extracted with 50 ml of ethyl acetate. After drying with anhydrous magnesium sulfate, this was subjected to concentration at reduced pressure and then purified with silicagel column chromatography, to prepare 7.7 g of the desired compound (3d) (purity: 97 %, yield: 98 %), as a colorless transparent oil. This was identical with standard sample in 1 H NMR(CDCl 3 ) spectrum.
  • the separated crystal was filtered and then washed with a small amount of cooled methanol, followed by vacuum drying to prepare 6.1 g of the desired compound (3e) (purity:. 95 %, yield: 97 %). Its melting point (113 to 115 °C) was similar to that of standard sample (115 °C).
  • the halogenating reaction was conducted in the same manner as in Example 1 except for the use of a starting material shown below and a chlorinating agent shown in Table 1, and the employment of reaction conditions shown in Table 2, to prepare the desired halogenide.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Saccharide Compounds (AREA)
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Claims (7)

  1. Procédé de préparation d'un composé halogéné de formule (3) A-X    dans laquelle A est un groupe alkyle à chaíne linéaire ou à chaíne ramifiée, qui peut être substitué, un groupe alcényle à chaíne linéaire ou à chaíne ramifiée, qui peut être substitué, un résidu aromatique monocyclique ou polycyclique qui peut être substitué, un résidu de stéroïde ou un résidu hétérocyclique monocyclique ou polycyclique qui peut être substitué, et X est un atome de chlore ou un atome de brome,
       comprenant la mise en réaction dans un solvant organique d'au moins un agent d'halogénation de formule (1)
    Figure 00390001
       dans laquelle X est tel que défini ci-dessus et Y est un ion chlore, un ion brome, un ion dichlorophosphate, un ion dibromophosphate, un ion chlorosulfonate, un ion bromosulfonate, un ion chlorooxalate ou un ion bromooxalate, avec un composé de formule (2) contenant un groupe hydroxyle A - OH    dans laquelle A est tel que défini ci-dessus.
  2. Procédé selon la revendication 1, dans lequel le composé (2) contenant un groupe hydroxyle est choisi parmi au moins un des composés (5) à (12) :
    composé (5) : alcool d'alkyle à chaíne linéaire ou à chaíne ramifiée dans lequel la partie alkyle a de 1 à 15 atomes de carbone et peut être substituée,
    composé (6) : alcool d'alcényle à chaíne linéaire ou à chaíne ramifiée dans lequel la partie alcényle a de 2 à 8 atomes de carbone et peut être substituée,
    composé (7) : 3-β-cholestérol,
    composé (8) : composés de formule (8) :
    Figure 00400001
       dans laquelle R5 à R8 sont identiques ou différents et sont chacun un atome d'hydrogène, un groupe alkyle en C1-C4, un groupe nitro, un groupe hydroxyle, un groupe carboxyle ou un groupe oxycarbonyle substitué,
    composé (9) : composés de formules (9a) à (9c) :
    Figure 00400002
       dans lesquelles R9 est un groupe alkyle en C1-C15 à chaíne linéaire ou à chaíne ramifiée, un groupe alcényle en C2-C8 à chaíne linéaire ou à chaíne ramifiée, un groupe cyclohexyle ou un groupe phényle ; et Ra est un atome d'hydrogène ou un groupe oxycarbonyle substitué,
    composé (10) : composés de formule (10) :
    Figure 00400003
       dans laquelle R10 est un atome d'hydrogène, un groupe amino ou un groupe amino protégé ; R11 est un atome d'hydrogène ou un groupe alcoxy en C1-C4, selon une autre possibilité R10 et R11 peuvent être liés entre eux pour former un groupe cyclique protégeant un groupe amino ; et R12 est un atome d'hydrogène ou un groupe protecteur d'acide carboxylique, et
    composé (11) : composés de formule (11) :
    Figure 00410001
       dans laquelle R13 à R16 sont identiques ou différents et sont chacun un atome d'hydrogène, un groupe alkyle en C1-C4, un groupe nitro, un groupe hydroxyle, un groupe carboxyle ou un groupe oxycarbonyle substitué ; et n vaut 1 ou 2,
    composé (12) : composé de formule XII :
    Figure 00410002
  3. Procédé selon la revendication 2, dans lequel le composé (2) contenant un groupe hydroxyle est au moins un composé choisi parmi les composés (5) à (10).
  4. Procédé selon la revendication 3, dans lequel le composé (2) contenant un groupe hydroxyle est au moins un composé choisi parmi les composés (7) à (10).
  5. Procédé selon la revendication 4, dans lequel le composé (2) contenant un groupe hydroxyle est au moins un composé choisi parmi les composés (9) et (10).
  6. Procédé selon la revendication 5, dans lequel le composé (2) contenant un groupe hydroxyle est un composé (10).
  7. Utilisation d'un halogénure de N,N-diéthylhaloiminium de formule (1)
    Figure 00420001
       dans laquelle X est un atome de chlore ou un atome de brome, et Y est ion chlore, un ion brome, un ion dichlorophosphate, un ion dibromophosphate, un ion chlorosulfonate, un ion bromosulfonate, un ion chlorooxalate ou un ion bromooxalate,
       en tant qu'agent d'halogénation.
EP98959149A 1998-02-17 1998-12-10 Procede d'halogenation de groupe hydroxyle Expired - Lifetime EP0976700B1 (fr)

Priority Applications (1)

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EP03003782A EP1319642B1 (fr) 1998-02-17 1998-12-10 Procédé de préparation d'un composé halogéné

Applications Claiming Priority (3)

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JP05273498A JP3202960B2 (ja) 1998-02-17 1998-02-17 ハロゲン化剤及び水酸基のハロゲン化方法
JP5273498 1998-02-17
PCT/JP1998/005579 WO1999041214A1 (fr) 1998-02-17 1998-12-10 Agent d'halogenation et procede d'halogenation de groupe hydroxyle

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EP0976700A4 EP0976700A4 (fr) 2001-04-11
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EP (2) EP0976700B1 (fr)
JP (1) JP3202960B2 (fr)
KR (1) KR100317425B1 (fr)
CN (1) CN1226245C (fr)
AT (2) ATE272050T1 (fr)
AU (1) AU1505399A (fr)
DE (2) DE69825262T2 (fr)
ES (2) ES2303874T3 (fr)
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WO (1) WO1999041214A1 (fr)

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CN114716296B (zh) * 2022-03-25 2023-12-12 润药仁智(北京)科技有限公司 一种烷基卤化物的高效卤化合成方法

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US3962227A (en) 1973-02-23 1976-06-08 Eli Lilly And Company 3-halo cephalosporins
US4447432A (en) * 1981-11-17 1984-05-08 Farmitalia Carlo Erba S.P.A. Azino rifamycins
US4568741A (en) * 1984-05-15 1986-02-04 The Upjohn Company Synthesis of 7-halo-7-deoxylincomycins
US4652644A (en) * 1985-04-29 1987-03-24 Bristol-Myers Company Process for preparation of N7 -amidino substituted mitomycin C derivatives

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HK1027089A1 (en) 2001-01-05
US6403789B1 (en) 2002-06-11
KR100317425B1 (ko) 2001-12-22
ATE390394T1 (de) 2008-04-15
WO1999041214A1 (fr) 1999-08-19
DE69825262D1 (de) 2004-09-02
EP1319642A2 (fr) 2003-06-18
KR20010006241A (ko) 2001-01-26
US6194567B1 (en) 2001-02-27
ES2303874T3 (es) 2008-09-01
EP1319642A3 (fr) 2003-12-03
DE69839315D1 (de) 2008-05-08
EP0976700A4 (fr) 2001-04-11
JP3202960B2 (ja) 2001-08-27
CN1226245C (zh) 2005-11-09
AU1505399A (en) 1999-08-30
ES2224452T3 (es) 2005-03-01
CN1252783A (zh) 2000-05-10
ATE272050T1 (de) 2004-08-15
EP1319642B1 (fr) 2008-03-26
DE69825262T2 (de) 2005-07-21
JPH11228452A (ja) 1999-08-24
DE69839315T2 (de) 2009-04-16
EP0976700A1 (fr) 2000-02-02

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